The University of Michigan Comprehensive Cancer Center (UMCCC) has taken on a leadership role in developing precision medicine approaches for oncology. In April of 2011, the MI-ONCOSEQ clinical sequencing program was established, which prospectively enrolls patients with advanced cancers for comprehensive mutational analysis using an integrative sequencing approach. Since establishment of this protocol, over 250 adults and 40 children with cancer have been sequenced with return of results through an institutionally sanctioned precision medicine tumor board (PMTB). Through support of the UM Prostate SPORE, Dr. Chinnaiyan and colleagues used this approach to establish the first mutational landscape of lethal castration resistant prostate cancer (CRPC) {Nature 2012). This Project will evaluate the mutational landscape of metastatic hormone sensitive prostate cancer (HSPC) along with CRPC, and thus, will employ precision medicine approaches for earlier stages of prostate cancer progression (i.e., prior to castration resistance). Furthermore, we will also explore mechanisms of resistance/progression in UMCCC-based clinical trials in metastatic prostate cancer as well as develop parallel in vitro tumoroid model systems. Thus, our Aims are as follows: Aim 1: Establish a precision medicine approach for patients presenting with metastatic HSPC. Here we will prospectively enroll patients seen in the UM High-Risk Clinic for prostate cancer to our clinical sequencing protocol. We plan to interrogate the germline exome and tumor exome/transcriptome (integrative sequencing) from men with Stage 4 prostate cancer to identify novel molecular alterations that may contribute to this clinical subset of patients. We will include metastatic HSPC patients who will be enrolled on a CDK4/6 inhibitor + androgen deprivation trial that is in the process of being activated at UM. Aim 2: Determine mechanisms of progression and resistance to therapy of men with metastatic CRPC. Here we will study the mutational landscape of patients with metastatic CRPC that will enroll in a targeted therapy trial to evaluate the tyrosine kinase inhibitor, cabozatanib. We will carry out integrative sequencing of the tumor specimens obtained at time of trial enrollment and at time of progression/recurrence. This will allow for one the first of its kind, temporal assessments of the mutational landscape of prostate cancer progression under targeted therapies. Aim 3: Establish prostate tumoroid cultures as a parallel model system in the precision medicine approach. These patient derived tumoroid cultures will be used to test predictions made by integrative sequencing.